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CLINICAL STATEMENTS AND GUIDELINES

April 1, 2025 Circulation. 2025;151:e771–e862. DOI: 10.1161/CIR.0000000000001309 e792

7 The clinical efficacy of prasugrel and ticagrelor com-

pared with clopidogrel in TRITON-TIMI 38 and the PLATO trial was consistent in patients undergoing PPCI or delayed (ie, secondary) PCI after initial therapy for STEMI.4,5 In the subgroup of patients with STEMI in TRITON-TIMI 38 (n=3534), prasugrel significantly reduced MACE by 21% and stent thrombosis by 42% at 15 months without a clear excess in bleeding.9 In the PLATO trial, compared with clopidogrel, treatment of patients with STEMI undergoing PPCI (n=7544) with ticagrelor was associated with a consistent trend toward reduction in cardiovascular death, recurrent MI, or stroke, as well as a significant reduction in stent thrombosis and an 18% reduction in all-cause death.10 Both TRITON-TIMI 38 and the PLATO trial permitted study drug administration prior to the initial angiogram for patients with STEMI undergoing primary PCI. In a separate randomized trial in PPCI for STEMI, allocation to prehospital ticagrelor or hospital administration did not improve the primary endpoint of coronary reperfusion prior to the PCI.25 However, upstream administration of ticagrelor was associated with a reduction in stent thrombosis with similar bleeding between treatment groups. Registry data have also not shown clear clinical benefit for preloading a P2Y12 inhibitor in patients with STEMI,26 but a meta-analysis that included patients with STEMI showed that clopidogrel pretreatment was associated with a lower risk for MACE without an increase in bleeding.27

8 Clopidogrel is effective for prevention of stent

thrombosis and early recurrent ischemic events in patients with STEMI undergoing PCI.11 As in patients with NSTE-ACS, in patients with STEMI undergoing PPCI, prasugrel and ticagrelor reduce the risk of recurrent MACE compared with clopidogrel.9,10 Administration of clopidogrel is an alternative to prasugrel or ticagrelor in patients with STEMI who are at high bleeding risk or have other contraindications to those agents. 9.	 In the CLARITY (Clopidogrel as Adjunctive

Reperfusions Therapy)-TIMI 28 trial, addition of clopidogrel to aspirin in patients with STEMI who were <75 years of age and received fibrinolytic therapy reduced the odds of an occluded infarct-related artery at angiography, as well as the composite of cardiovascular death, recurrent MI, or recurrent ischemia requiring urgent revascularization by 30 days.2 In the randomized, placebo-controlled COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) study among patients with suspected MI (93% STEMI, 54% fibrinolytic-treated) receiving aspirin, clopidogrel 75 mg/day (without a loading dose), significantly lowered the risk of the composite endpoint of death, reinfarction, or stroke, as well as the endpoint of mortality alone, with a consistent pattern in the subgroup treated with fibrinolytic.3 No significant excess was observed in bleeding with clopidogrel versus placebo. Based on the design of these 2 trials, when administered concurrently with fibrinolytic as the reperfusion strategy, clopidogrel is recommended to be administered with a loading dose (300 mg, then 75 mg daily) for patients <75 years of age and starting without a loading dose (75 mg daily) for patients ≥75 years of age. In patients treated with a fibrinolytic agent who are undergoing subsequent PCI, either clopidogrel or ticagrelor (age <75 years, within 24 hours after a fibrinolytic agent) or prasugrel (>24 hours after a fibrinolytic agent) are alternatives to support PCI.9–12,28 In a trial of 3799 patients with STEMI who were treated with a fibrinolytic agent, 89% of whom also received clopidogrel at the time of a fibrinolytic agent, randomization to ticagrelor administered at a median of 11.4 hours (interquartile range, 5.8-18.2 hours) after fibrinolytic therapy was noninferior to clopidogrel with respect to major bleeding.28

4.3.3 Intravenous P2Y12 Inhibition

Recommendation for Intravenous P2Y12 Inhibition Referenced studies that support recommendations are summarized in the Evidence Table.

COR LOE Recommendation

2b B-R 1 Among patients with ACS undergoing PCI who

have not received a P2Y12 inhibitor, intravenous cangrelor may be reasonable to reduce periprocedural ischemic events.*1–4

*Reproduced from the “2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization.”5

Synopsis Cangrelor is a direct-acting, intravenous antagonist of the P2Y12 receptor characterized by rapid and potent platelet inhibitory effects with restoration of platelet function occurring within 1 hour of drug discontinuation.6 These pharmacological properties may be particularly beneficial in clinical scenarios wherein absorption of orally administered P2Y12 inhibitors is impaired or not possible, as well as in patients requiring CABG or other surgery early after PCI when prolonged discontinuation of a P2Y12 inhibitor may not be safe.7 The safety and efficacy of cangrelor has been compared with clopidogrel or placebo in 3 RCTs involving patients who are P2Y12 inhibitor-naïve and undergoing PCI for stable or acute indications.1–3 In a patient-level pooled analysis of these studies, cangrelor administered during PCI significantly reduced periprocedural ischemic events albeit at the expense of more frequent minor bleeding.4 The safety and efficacy of cangrelor versus ticagrelor or prasugrel with respect to ischemic events have not been established. The transition from intravenous to oral P2Y12 inhibition is an important consideration to ensure adequate platelet inhibition on completion of cangrelor infusion (Table 9).8

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